Metal-free DDQ-mediated oxidative C-O coupling of acetalic sp3 C-H bonds with carboxylic acids

Article abstract of DOI:10.1039/c4ra08627a

A simple and efficient DDQ-mediated oxidative C-O coupling reaction between acetalic sp³ C-H and carboxylic acid O-H bonds has been developed. This novel transformation smoothly proceeds without any metal catalyst and allows for the highly efficient synthesis of (un)symmetric glycol diesters in a single step. This journal is

Full text of DOI:10.1039/c4ra08627a

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Metal-free DDQ-mediated oxidative C–O coupling
of acetalic sp3 C–H bonds with carboxylic acids†
Cite this: RSC Adv., 2014, 4, 54039
a
a
a
a
Jiang-Sheng Li, Yuan Xue, Dong-Mei Fu, Dao-Lin Li, Zhi-Wei Li, a Wei-Dong Liu,b
*
*
Huai-Lin Pang,b Yue-Fei Zhang,a Zhong Caoa and Ling Zhanga
Received 13th August 2014
Accepted 24th September 2014
DOI: 10.1039/c4ra08627a
www.rsc.org/advances
A simple and efficient DDQ-mediated oxidative C–O coupling reac- coupling between acetalic sp3 C–H bonds and carboxylic
tion between acetalic sp3 C–H and carboxylic acid O–H bonds has acids using DDQ without the presence of any metal catalyst
been developed. This novel transformation smoothly proceeds (Scheme 1).
without any metal catalyst and allows for the highly efficient synthesis
We set about our evaluation of the reaction parameters with
2-phenyl-1,3-dioxolane (1a) and benzoic acid (2a) as standard
substrates using DDQ as dehydrogenative reagent and the
results are compiled in Table 1. First, the reaction was per-
of (un)symmetric glycol diesters in a single step.
ꢀ
Carboxylic acid esters are ubiquitous in nature and serve as an
important building block in organic synthesis and chemical
industry.1 Their traditional preparative methods2 usually
require strongly acidic catalysts, expensive dehydrating agents,
and even produce undesired byproducts. With the booming of
C–H functionalization,3 novel oxidative esterication of
carboxylic acids with hydrocarbons via C–H activation has been
developed.4 However, to the best of our knowledge, it focuses on
the synthesis of monoesters. In fact, glycol diesters also widely
occur in pharmaceuticals,5 such as binibrate, diniprofylline,
and etobrate (Fig. 1).
They are commonly formed by esterication of alcohols with
carboxylic acids/activated carboxylic acid derivatives, or alkyl-
ation of carboxylate anions. However, the synthesis of unsym-
metric diesters is a challenging issue. Therefore, methods for
the direct and efficient synthesis of glycol diesters, especially
unsymmetric ones, are still in high demand. Recently, our
group has reported the DDQ-mediated domino cross-
dehydrogenative coupling (CDC)6 reaction of cyclic acetals
with simple ketones,7 which suggested that cyclic acetals could
be an excellent acyloxyethyl synthon under oxidative conditions.
On the basis of the continued interest in acetalic C–H func-
tionalization, we herein present the efficient oxidative C–O
formed in a series of solvents at 80 C. When the reaction was
conducted in CH3NO2, and CH3CN, it afforded the desired
product 3aa in low yield (Table 1, entries 1 and 2). However, 3aa
was obtained in high yield in EtOAc, CHCl3, 1,2-dichloroethane
(DCE), benzene, and CH2Cl2 (Table 1, entries 3–7). Among these
solvents, CH2Cl2 was the best choice, giving the highest yield of
90% (Table 1, entry 7). When the coupling reaction was per-
formed at lower temperatures such as 60 ꢀC, and 40 ꢀC, the yield
decreased dramatically (Table 1, entry 8 and 9). Additionally, the
equivalents of 1a and DDQ were examined. Increasing either of
them led to no obvious improvement (Table 1, entry 10 and 11),
whereas decreasing the amount of 1a resulted in the incomplete
consumption of 2a obtaining only a 68% yield (Table 1, entry
12). Thus, the optimized reaction conditions for the oxidative
aSchool of Chemistry and Biological Engineering, Changsha University of Science &
Technology, Changsha 410114, People's Republic of China. E-mail: jslichem@gmail.
com; lizwhn@126.com; Fax: +86-731-85258733
bNational Engineering Research Center for Agrochemicals, Hunan Research Institute of
Chemical Industry, Changsha 410007, People's Republic of China
† Electronic supplementary information (ESI) available. CCDC 1009912. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra08627a
Fig. 1 Selected examples of glycol diesters.
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Table 2 DDQ-mediated oxidative C–O coupling of cyclic acetals 1
with carboxylic acids 2
Scheme 1 Oxidative C–O coupling reaction of the acetalic sp3 C–H
bond with a carboxylic acid.
Entrya
R1
R2
3
Yieldb (%)
Table 1 Optimization of the reaction conditions for 3aa
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
90
74
87
83
92
93
91
72
94
86
72
73
87
81
74
93
86
0
2-MeC6H4
3-MeOC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
3,4-Di-NO2C6H3
E-PhCH]CH
2-furyl
Entrya
1ab
Solventc
T (ꢀC)
Yieldd (%)
9
Ph
Ph
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
3
2
1
CH3NO2
CH3CN
EtOAc
CHCl3
DCE
Benzene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
80
80
80
80
80
80
80
60
40
80
80
80
10
12
65
88
76
72
90
78
57
90
91
68
10
11
12
13
14
15
16
17
18
H
3aj
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
H
2-MeC6H4
2-MeOC6H4
4-ClC6H4
2-MeC6H4
2-MeOC6H4
2-ClC6H4
4-ClC6H4
Ph
3bb
3bk
3be
3cb
3ck
3cf
3ce
3da
9
10
11e
12
a
Standard reaction conditions for diesters: 1 (2 mmol), 2 (1 mmol) and
b
DDQ (1.2 mmol) in CH2Cl2 (4 mL) for 12 h. Isolated yield.
a
Reaction conditions: 1a, 2a (1 mmol) and DDQ (1.2 mmol) in solvent (4
b
c
d
mL) for 12 h. 1a (mmol). Dried using standard methods. Isolated
yield based on 2a. DDQ (1.5 mmol) used.
e
yields. All the functional groups involved were also considered.
As mentioned earlier, the acids with lower pKa values resulted in
higher yields. Unfortunately, 1,3-dioxolane could not yield the
desired coupled product (Table 2, 3da).
transformation were acetal (2.0 equiv.), DDQ (1.2 equiv.) in
CH2Cl2 in a sealed tube at 80 C for 12 h.
Aer the investigation of aromatic and aliphatic carboxylic
acids, we further attempted the reaction of acetals with 2-aryl
acetic acids, as coupling partners, under standard conditions
(Scheme 2). The products were obtained in moderate yields. To
our surprise, however, it was found that their NMR spectra
indicated the presence of benzoate and ethylene moieties, but a
lack of signals for CH2 protons and C atom of 2-aryl acetic
acids,8 which were essentially identical for those of 3aa, 3ae, 3af,
and 3cf produced from the corresponding benzoic acids.
Furthermore, the structure of the coupled product of 1c with 2-
ꢀ
Under the optimized reaction conditions, various carboxylic
acids 2 combined with 2-phenyl-1,3-dioxolane were tested,
providing the corresponding (un)symmetric glycol diesters 3
(Table 2, entries 1–10). The data in Table 2 show that the yields
were good to excellent. This oxidative C–O coupling was
compatible with different Me, OMe, Cl, and NO2 groups on the
benzene ring. Notably, steric effects of the substituents had
little inuence on the yields (Table 2, 3ab and 3af). However,
slight electronic effects of the substituents were observed. The
presence of electron-withdrawing groups favored the oxidative
coupling reaction (Table 2, 3ae, 3af and 3ag). Fortunately, cin-
namic acid and 2-furoic acid could also be readily introduced in
the transformation (Table 2, 3ah and 3ai). However, no reac-
tions occurred for the tested aliphatic carboxylic acids such as
acetic acid, propionic acid, hexanoic acid, and cyclo-
hexanecarboxylic acid except for formic acid that delivered the
coupled diester 3aj in a 86% yield. Probably, the pKa values of
the carboxylic acids 2 could well account for these experimental
results.
Next, several cyclic acetals 1b–d were also tested in this
oxidative transformation (Table 2, entries 11–18). 2-Aryl-1,3-
dioxolanes could react satisfactorily with aromatic carboxylic
Scheme 2 DDQ-mediated oxidative C–O coupling of 1 with 2-aryl
acids 2 to afford unsymmetric diesters in good to excellent acetic acids.
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Scheme 5 Plausible mechanism.
Fig. 2 X-ray crystal structure of the diester 3cm.
oxidized to a 1,3-dioxonium ion and to a DDQHÀ anion. H-atom
abstraction of carboxylic acid 2 by DDQHÀ and subsequent
nucleophilic attack at the C-4/5 rather than the C-2 position by
carboxylic anion produces the C–O coupled product 3 together
with the reduced hydroquinone DDQH2.
In conclusion, we have demonstrated an efficient DDQ-
mediated oxidative cross-coupling reaction between acetalic
sp3 C–H and carboxylic acid O–H bonds. This novel protocol
makes cyclic acetals excellent acyloxyethyl synthons under
oxidative conditions, and further achieves short reaction steps,
good functional group tolerance, and good to excellent yields.
Most importantly, it allows for the highly efficient synthesis of
unsymmetric glycol diesters in one step. Further investigation
of acetalic C–H functionalization is ongoing in our laboratory.
(2-chlorophenyl) acetic acid was conrmed by single-crystal X-
ray experiments (Fig. 2).9
Alkylation is an important transformation in organic
synthesis.10 The direct O-alkylation of carboxylic acid is an
alternative strategy toward the construction of carboxylic
esters.2 On the basis of the results mentioned above, we
reasoned that acyclic acetals, such as dimethoxymethane or
diethoxymethane, would be likely to be alkylating agents in the
oxidative coupling reactions.
Based on this hypothesis, we examined the reaction of 1e, 1f
with 2a, respectively, under standard conditions (Scheme 3). To
our disappointment, 2a was recovered quantitatively, and no
desired benzoates were detected by TLC analysis, even though
the equivalents of 1e or 1f amounted up to 10.
To gain insight into the mechanism of this novel oxidative
C–O coupling protocol, the radical scavenger TEMPO was added
to the standard reaction system to monitor whether radical
species are formed (Scheme 4). The reaction was partially
inhibited by 2 equivalents of TEMPO, and 3aa was isolated in a
36% yield, indicating that this transformation may involve
radical intermediates.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21202010, 21376031 & 21275022), the
Hunan Provincial Natural Science Foundation of China
(12JJ4021) and Hunan Provincial Science and Technology
Project (2013NK3002).
The proposed mechanism is depicted in Scheme 5. The
reaction might be initiated by a single electron transfer (SET)
oxidation to form an acetal radical, which can be further
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